YTHDF 蛋白在调节 mA 修饰 mRNA 功能中的统一模型
A Unified Model for the Function of YTHDF Proteins in Regulating mA-Modified mRNA.
机构信息
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
出版信息
Cell. 2020 Jun 25;181(7):1582-1595.e18. doi: 10.1016/j.cell.2020.05.012. Epub 2020 Jun 2.
Abstract
N-methyladenosine (mA) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. mA is thought to mediate its effects through a complex network of interactions between different mA sites and three functionally distinct cytoplasmic YTHDF mA-binding proteins (DF1, DF2, and DF3). In contrast to the prevailing model, we show that DF proteins bind the same mA-modified mRNAs rather than different mRNAs. Furthermore, we find that DF proteins do not induce translation in HeLa cells. Instead, the DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation. The ability of DF proteins to regulate stability and differentiation becomes evident only when all three DF paralogs are depleted simultaneously. Our study reveals a unified model of mA function in which all mA-modified mRNAs are subjected to the combined action of YTHDF proteins in proportion to the number of mA sites.
摘要
N6-甲基腺苷（m6A）是最丰富的 mRNA 核苷酸修饰，调节细胞生理和分化的关键方面。m6A 被认为通过不同 m6A 位点与三种功能不同的细胞质 YTHDF m6A 结合蛋白（DF1、DF2 和 DF3）之间的复杂相互作用网络来发挥其作用。与流行的模型相反，我们表明 DF 蛋白结合相同的 m6A 修饰的 mRNA，而不是不同的 mRNA。此外，我们发现 DF 蛋白不会诱导 HeLa 细胞中的翻译。相反，DF 蛋白同工型冗余地发挥作用以介导 mRNA 降解和细胞分化。只有当同时耗尽所有三个 DF 蛋白同工型时，DF 蛋白调节稳定性和分化的能力才变得明显。我们的研究揭示了 m6A 功能的统一模型，其中所有 m6A 修饰的 mRNA 都受到 YTHDF 蛋白的共同作用，其比例与 m6A 位点的数量成正比。
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2
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Nat Rev Mol Cell Biol. 2019 Oct;20(10):608-624. doi: 10.1038/s41580-019-0168-5. Epub 2019 Sep 13.
3
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8
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9
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